The present invention relates to implantable sensors, and more specifically, to implantable sensors for monitoring levels of analytes, such as glucose.
Several designs for implantable sensors that allow continuous in vivo monitoring of levels of analytes such as glucose have been previously described. Many such designs are based on electrochemical analyte detection principles. As such, they are prone to inherent signal instability of the sensor, and they require that chemicals (e.g., enzymes and mediators) be introduced into the patient's body.
A second approach involves physical (i.e. reagent-free) methodology. A review of physical methods for determinations of glucose in vivo is given in J. D. Kruse-Jarres “Physicochemical Determinations of glucose in vivo,” J. Clin. Chem. Clin. Biochem. 26 (1988), pp. 201-208. Nuclear magnetic resonance (NMR), electron spin resonance (ESR), and infrared (IR) spectroscopy are named, among others, as non-invasive methods. However, none of these methods has as yet acquired practical significance. Some of them require large and expensive apparatus, generally unsuitable for routine analysis and home monitoring of a patient.
Nearly all of the methods of this second approach are based on spectroscopic principles. Concerning the optical methods, the fundamental principle frequently is the interaction of the irradiated primary light (of a specific wavelength) with the vibration and rotation states of the molecules undergoing analytical determination. The basic vibrational and rotational states of glucose are found in the IR region at wavelengths above 2500 nm. This spectral region is not suitable for invasive analytical determination of glucose because of the strong absorption of water, which is present in high concentration in biological matrices. In the near infra-red (NIR) region, the absorption of water is smaller (the so-called “water transmission window). The spectral analysis of glucose in this region is based on absorption by overtones and combination oscillations of the basic vibrational and rotational states of the glucose molecule (see the article by Kruse-Jarres cited above and EP-A-0 426 358).
Developing a practical implantable glucose sensor on the basis of these principles presents certain problems. These problems result particularly from the fact that the effective signal (the change in the absorption spectrum due to a change in glucose concentration) is generally very small. Sensitivity is always an issue in absorption measurements because of the difficulty in observing a small effective signal superimposed on a relatively much larger background signal. However, in this case the difficulty is enhanced due to background signals resulting from the spectral absorption of water. Some attempts have been made to solve this problem (see e.g., EP-A-0 160 768; U.S. Pat. No. 5,028,787; and WO 93/00856); however, these attempts have not been successful in providing a practical and functional implantable glucose sensor based on absorption principles.
Methods of continuously monitoring glucose based on light scattering principles have also been described. For instance, European patent 0 074 428 describes a method and device for the quantitative determination of glucose by laser light scattering. The method assumes that glucose particles scatter light rays transmitted through a test solution, and that the glucose concentration can be derived from this scattering. The method requires measurement of the spatial angular distribution of the transmitted (i.e. forward-scattered) light emerging from a test cuvette or an investigated part of the body. In particular, the intensity of the transmitted light is measured in an angular region in which the change in relation to the glucose concentration is as large as possible. This intensity is then compared with the intensity measured for the central ray passing directly through the sample. For in vivo analytical determination, a transmission measurement on ear lobes with laser light is exclusively recommended.
A second method based on light scattering principles relies on the measurement of back-scattered light rather than transmitted (i.e. forward-scattered) light. U.S. Pat. No. 5,551,422 describes a method for determining glucose concentration in a biological matrix by performing at least two detection measurements. In each detection measurement, primary light is irradiated into the biological matrix through a boundary surface thereof at a defined radiation site. The light is propagated along a light path within the biological matrix. An intensity of the light is measured as the light emerges as secondary light through a defined detection site of the boundary surface. At least one of the detection measurements is a spatially resolved measurement of multiply scattered light. The detection site is located relative to the irradiation site such that light which was multiply scattered at scattering centers in the biological matrix is detected. The light paths of the at least two detection measurements within the biological matrix are different. Glucose concentration is then derived from the dependence of the intensity of the secondary light on the relative positions of the irradiation site and the detection site.
Additional methods are needed which minimize or eliminate the effect on light intensity from variations of physical parameters, such as temperature and/or changes in the concentrations of background ions, proteins, and organic acids in the biological matrices, and which minimize the number of light paths and/or detection measurements required to be performed.